Development and pharmacological characterization of conformationally constrained urotensin II-related peptide agonists

J Med Chem. 2013 Dec 12;56(23):9612-22. doi: 10.1021/jm401153j. Epub 2013 Nov 26.


Urotensin II (UII) and its paralog peptide, urotensin II-related peptide (URP), exert not only common but also divergent actions through the activation of UT, a specific membrane-bound receptor that belongs to the 1A G protein-coupled receptor subclass. In this study, we have designed and synthesized new URP analogues in which the intracyclic Trp residue was replaced with natural, unnatural, and constrained amino acids to determine important physicochemical features for receptor binding and activation. The biological data, highlighting the potent agonistic behavior of [Tiq(4)]URP and [Tpi(4)]URP, also suggest that the Trp residue, and more specifically the indole ring, is not critical for receptor interaction and could in fact be involved in the intramolecular stabilization of the bioactive conformation of URP. Finally, these analogues, which are intracyclic constrained URP-based agonists, could represent useful pharmacological tools for the study of the urotensinergic system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Molecular Dynamics Simulation
  • Peptide Hormones / agonists*
  • Peptide Hormones / chemistry
  • Peptide Hormones / pharmacology
  • Rats
  • Urotensins / antagonists & inhibitors
  • Vasoconstriction / drug effects


  • Intracellular Signaling Peptides and Proteins
  • Peptide Hormones
  • UTS2B protein, human
  • Urotensins
  • urotensin II